The Role Of Interferon Gamma And Nitric Oxide As Downregulating Molecules In Central Nervous System Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$526,644.00
Summary
Cytokines are soluble factors which participate in inflammatory responses. Interferon gamma is a cytokine which in the context of central nervous system inflammation has been considered a Obad? molecule, as has the gas nitric oxide which is induced by interferon gamma. We now have direct evidence that indicate quite the contrary, ie interferon gamma and nitric oxide can a do act as down regulators of inflammation. The present work is designed to determine if this down regulating function is rest ....Cytokines are soluble factors which participate in inflammatory responses. Interferon gamma is a cytokine which in the context of central nervous system inflammation has been considered a Obad? molecule, as has the gas nitric oxide which is induced by interferon gamma. We now have direct evidence that indicate quite the contrary, ie interferon gamma and nitric oxide can a do act as down regulators of inflammation. The present work is designed to determine if this down regulating function is restricted only to a single model of CNS inflammation or is a general phenomenon within the CNS. The project will also involve a number of experiments designed to elucidate the mechanism(s) by which down regulation occurs. This project is highly significant in that a single uncontrolled clinical trial of interferon gamma for the therapy of MS has been carried out and reported as indicating that interferon gamma made the disease worse. The design of that trial however was such that the validity of that claim is questionable. If our experiments confirm the general nature of interferon gamma as a down regulator in inflammation in a number of different models of MS then a case for revisiting the use of interferon, or a downstream product of interferon, in the therapy of MS might be made.Read moreRead less
Pharmacological Strategies To Prevent Damage To White Matter In The Central Nervous System After Ischaemia
Funder
National Health and Medical Research Council
Funding Amount
$150,770.00
Summary
A stroke is caused by an acute blockade of blood flow to a brain region and in most cases, is caused by a clot in the artery that supplies the oxygenated blood and nutrients such as glucose to that region. Within minutes, the region of the brain that is deprived of blood flow will die and so the functions controlled by that region are lost. In the majority of stroke patients, the middle cerebral artery is blocked and this affects parts of the brain controlling movement of limbs or speech and so ....A stroke is caused by an acute blockade of blood flow to a brain region and in most cases, is caused by a clot in the artery that supplies the oxygenated blood and nutrients such as glucose to that region. Within minutes, the region of the brain that is deprived of blood flow will die and so the functions controlled by that region are lost. In the majority of stroke patients, the middle cerebral artery is blocked and this affects parts of the brain controlling movement of limbs or speech and so these patients suffer permanent disabilities. Not surprisingly, stroke is the most common life-threatening neurological disease and the major cause of disbility in adults over 45 years of age. Apart from the profound effect that stroke has on the patient and family, the annual cost of disability to the Australian community is approximately $ 1 billion. If the disability could be reduced, this could reduce the need for institutionalisation of patients and then the cost saving would be great. So our research is directed towards designing drugs to minimise the disability after stroke. Research in the past has focussed on designing drugs to minimise damage to the grey matter in brain but it is becoming apparent that the white matter in brain is very important for transmitting information and also needs to be protected. We will study the biochemical changes in white matter after a stroke in a rat model and use this information to design in a rational way, novel drugs to minimise damage to white matter (axons), thereby reducing the degree of disability after a stroke.Read moreRead less
The Role Of BDNF In Central Nervous System Myelination
Funder
National Health and Medical Research Council
Funding Amount
$478,235.00
Summary
Multiple Sclerosis (MS) is the most common neurological cause of disability in young adult Australians. The cause of MS is unknown and therapies are limited to reducing inflammation, which does not address the major problem of the disease: loss of myelin. This project directly investigates how myelin is formed and will identify key mechanisms in this process, which may eventually be developed into treatments for diseases such as MS.
T Cell Apoptosis In Multiple Sclerosis And Experimental Autoimmune Encephalomyelitis
Funder
National Health and Medical Research Council
Funding Amount
$299,950.00
Summary
Multiple sclerosis is a disease of the nervous system and is a common cause of disability in young adults. There is increasing evidence that multiple sclerosis is caused by repeated attacks on the nervous system by the white blood cells (lymphocytes) of the body's own immune system. A major unanswered question in multiple sclerosis is why repeated immune attacks on the nervous system occur. I have recently proposed that the repeated nature of the immune attacks in multiple sclerosis results from ....Multiple sclerosis is a disease of the nervous system and is a common cause of disability in young adults. There is increasing evidence that multiple sclerosis is caused by repeated attacks on the nervous system by the white blood cells (lymphocytes) of the body's own immune system. A major unanswered question in multiple sclerosis is why repeated immune attacks on the nervous system occur. I have recently proposed that the repeated nature of the immune attacks in multiple sclerosis results from a failure of the mechanism that switches off immune attacks on the nervous system in healthy individuals. In an animal model of multiple sclerosis we have shown that the lymphocytes attacking the nervous system rapidly commit suicide in the nervous system by a process known as apoptosis, and that this is associated with switching off of the immune attack and recovery from the disease. The present project aims to study further this process of lymphocyte suicide in experimental animals by determining whether the lymphocyte suicide is mediated through a death receptor molecule named Fas (CD95). The project will also investigate the process of lymphocyte suicide in white blood cells obtained from patients with multiple sclerosis to determine if this process is defective and to determine whether these patients have abnormalities in the Fas molecular pathway. This project will shed light on the question of why repeated immune attacks on the nervous system occur in multiple sclerosis, and has the potential to lead to the development of new treatments for multiple sclerosis.Read moreRead less
Pathogenesis Of Inflammatory Demyelinating Polyneuropathy
Funder
National Health and Medical Research Council
Funding Amount
$421,980.00
Summary
This project will investigate the cause of Guillain Barre syndrome (GBS), a severe disease that causes paralysis of the limbs, and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), a similar disease that causes either repeated attacks of weakness or chronic weakness. These are important diseases of the peripheral nervous system. In GBS and CIDP, white blood cells move from the bloodstream to phagacytose (eat) the myelin that surrounds peripheral nerve fibres. Removal of myelin interferes ....This project will investigate the cause of Guillain Barre syndrome (GBS), a severe disease that causes paralysis of the limbs, and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), a similar disease that causes either repeated attacks of weakness or chronic weakness. These are important diseases of the peripheral nervous system. In GBS and CIDP, white blood cells move from the bloodstream to phagacytose (eat) the myelin that surrounds peripheral nerve fibres. Removal of myelin interferes with normal function of the nerves. The project will investigate 5 aspects of GBS and CIDP. (1) We will determine which component of myelin is recognised by white blood cells from patients with GBS and CIDP. We have performed preliminary studies indicating that a protein known as PMP-22 and gangliosides may be targets of the immune attack, but this needs to be confirmed. (2) We will study how the immune attack is turned off in GBS. (3) We will study whether and why the immune attack fails to be turned off in CIDP. (4) We will identify genetic markers that may predispose to GBS and CIDP. (5) We will investigate a novel animal model of GBS that we have induced in rats by inoculation with fragments of PMP-22 protein.Read moreRead less
The Role Of BMP4 Signalling In Oligodendrogenesis Following Central Demyelination
Funder
National Health and Medical Research Council
Funding Amount
$360,202.00
Summary
Multiple Sclerosis (MS) is the most common neurodegenerative disease affecting young adults. It is a disease that kills myelin cells, which are necessary support cells for neurons and are critical for their function. This research investigates the role that BMPs play in myelin cell production and repair. Our aim is to identify regenerative therapeutics for MS.
Interrogation Of Two Novel Genetic Susceptibility Loci For Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$840,615.00
Summary
This proposal, from the Australia and New Zealand multiple sclerosis (MS) Genetics Consortium, aims to interrogate two new genes that it recently identified as predisposing for the development of MS. Both of the genes underlying these findings are also associated with risk of developing other autoimmune diseases such as type 1 diabetes, rheumatoid arthritis and Graves' disease.
Identifying Genes In The HLA Complex That Influence Clinical Course And Susceptibility In Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$725,177.00
Summary
There is no cure for multiple sclerosis (MS), but a person's genetic make-up can influence their susceptibility to developing MS and the symptoms of their condition. Knowing more about these MS genes will help to a) provide better advice concerning a person's risk of developing the disease or their prognosis b) in the design of new treatments. This project aims to identify 'MS genes in a region of the human genome call the HLA complex.
Mechanisms Of Lesion Localization In Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$411,228.00
Summary
Multiple sclerosis (MS) is a chronic disease that affects all areas of the brain and spinal cord (central nervous system or CNS), leading to a huge variety of clinical symptoms and signs, depending upon which parts of the CNS are affected. MS affects about 2 million people worldwide, with the onset of disease often between 20-40 years of age, at a time when family and work commitments are often at their peak. There is no cure for MS, and most people who develop this disease become more and more ....Multiple sclerosis (MS) is a chronic disease that affects all areas of the brain and spinal cord (central nervous system or CNS), leading to a huge variety of clinical symptoms and signs, depending upon which parts of the CNS are affected. MS affects about 2 million people worldwide, with the onset of disease often between 20-40 years of age, at a time when family and work commitments are often at their peak. There is no cure for MS, and most people who develop this disease become more and more disabled over their lifetime. MS is an autoimmune disease, i.e. one's own immune system starts to see the CNS as something foreign that needs to be targetted and eliminated. Previously, it has been considered that there are no particular reasons why people with MS develop lesions in the specific parts of the CNS that they do, i.e. it has been thought to be a fairly random event. However, we have recently shown that there are clear correlations between the development of lesions in some parts of the CNS, the particular molecules within the CNS that are being targetted by the immune system, and some genes that control the immune system that are carried by people with MS. The aim of the current study is to work out the mechanism(s) by which autoimmune reactivity targets lesions to different parts of the CNS. We will focus on one target molecule known as myelin proteolipid protein or PLP. People with MS who carry certain immune-related genes are more likely to have immune cells that target PLP, and our work strongly suggests that this subsequently leads to the development of lesions in the brainstem or cerebellum. This work has implications for disease pathogenesis, prognostication and therapy for MS, as a knowledge of patterns of autoimmune reactivity that lead to particular clinical outcomes will improve our ability to give people with MS an idea of they symptoms they might experience and allow specific therapies to be given to patients who will benefit most from them.Read moreRead less
After The Cloning Of The HMSNL Gene: Molecular Pathogenesis Of The Disease
Funder
National Health and Medical Research Council
Funding Amount
$258,564.00
Summary
We have completed an NHMRC-funded study, where we identified the gene for a severe disorder of the peripheral nervous system. The disease, hereditary motor and sensory neuropathy - Lom (HMSNL), presents with gait disturbances, difficulty in using the hands, muscle weakness and wasting and sensory loss. The concomitant impairment of the insulating myelin sheath surrounding nerve fibres (facilitating nerve conduction) and of the nerve fibres themselves suggests that the molecular defect lies in th ....We have completed an NHMRC-funded study, where we identified the gene for a severe disorder of the peripheral nervous system. The disease, hereditary motor and sensory neuropathy - Lom (HMSNL), presents with gait disturbances, difficulty in using the hands, muscle weakness and wasting and sensory loss. The concomitant impairment of the insulating myelin sheath surrounding nerve fibres (facilitating nerve conduction) and of the nerve fibres themselves suggests that the molecular defect lies in the basic mechanisms of interaction between the two main types of cell in the peripheral nervous system: the myelin-producing Schwann cell and the neuron. The two cells form the most complex system of communication in the human body, where signaling from one is vital for the development, functioning and survival of the other. Very little is known about the molecular mechanisms of this communication. At the same time, knowledge of the normal mechanisms of interaction is the key to better understanding of the mechanisms of disease in the peripheral nervous system and of the causes and possible prevention of the impairment of function. The newly identified HMSNL gene is probably involved in the signaling necessary for the development and functioning of the Schwann cell and for the survival of the nerve fibres. To gain an insight into the nature of the signaling cascade, we propose to use several complementary experimental approaches. We will create a mouse model of the human disease, to study its very early stages and subsequent evolution. In parallel, we will use molecular techniques and a yeast model, to identify other steps in the signaling cascade. The NHMRC-funded study will be part of a larger project conducted in collaboration with leading laboratories in the UK and the Netherlands, where other aspects of the molecular basis of the disease and of the role of the new gene will be examined.Read moreRead less